ADMET and DMPK最新文献

Introduction: Curcumin, a polyphenolic bioactive molecule, exhibits potent anti-inflammatory and antioxidant properties by reducing cytokine levels such as IL-6, TNF-α, and TGF-β. It regulates IL-17A and modulates key signaling pathways, including PI3K/AKT/mTOR, NF-κB and JAK/STAT. However, its clinical application is hindered by rapid metabolism, poor solubility, and chemical instability.

Method: Using the Box-Behnken design, this study developed and optimized a curcumin-loaded turmeric oil-based nanoemulsion system. The effects of turmeric oil, Tween 80 and sonication cycles on particle size (PS), polydispersity index (PDI), and encapsulation efficiency were analyzed. The optimized nanoemulsion was characterized by zeta potential, PDI, PS, morphology, loading efficiency, EE, and antioxidant activity (DPPH assay). In vitro cytotoxicity was evaluated using A549 cells, while in vivo efficacy was assessed in BALB/c mice through histological analysis, bronchoalveolar lavage fluid analysis, and TNF-α and IL-1β estimation via enzyme-linked immunosorbent assay.

Results: The optimized nanoemulsion had high entrapment efficiency (92.45±2.4 %), a PS of 130.6 nm, a PDI of 0.151, and a zeta potential of -1.7±0.6 mV. Nanoparticle tracking analysis confirmed a mean PS of 138.3±1.6 nm with a concentration of 3.78×10¹² particles/mL. Transmission electron microscopy imaging confirmed spherical morphology. The IC ₅₀ value was 25.65 μg/mL. The nanoemulsion remained stable for three months at 4±1 and 25±2 °C/ 60±5 % relative humidity. The optimized formulation significantly reduced BALF total cell count, alveolar wall thickening, and TNF-α and IL-1β levels (p < 0.001).

Conclusion: Overall, the optimized formulation significantly lowered levels of pro-inflammatory cytokines in the acute lung injury /acute respiratory distress syndrome mouse model.

Background and purpose: The use of drug delivery systems to enhance the efficacy of existing antimicrobial drugs is one of the promising approaches to combat bacterial resistance. The simultaneous presence of a polycationic biopolymer (chitosan) and an antibacterial drug (ceftazidime) in polyhydroxyalkanoates microparticles is more effective since it allows such carriers to have a more pronounced therapeutic effect. In this study, chitosan-modified ceftazidime-loaded poly(3-hydroxybutyrate-3-hydroxyvalerate-3-hydroxyhexanoate) (P(3HB-3HV-3HHх)) microparticles were prepared and investigated as a drug delivery system.

Experimental approach: The obtained microparticles were characterized in terms of their particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency, drug release studies in vitro, cytotoxicity and antibacterial properties in cell cultures.

Key results: The microparticles had spherical shapes with diameters from 0.6 to 1.6 μm. The constructed chitosan-modified ceftazidime-loaded microparticles are a depot form of drug, the release of which in vitro is realized for a long time, without burst releases, corresponds to Korsmeyer-Peppas and Higuchi models. In vitro cell viability and proliferation studies on designed microparticles investigated using HaCaT (human keratinocyte skin cell lines) showed good cell proliferation. The hemolytic activity of chitosan-modified P(3HB- 3HV-3HHх) microparticles evaluated by hemolysis assay demonstrated good blood compatibility. Chitosan-modified microparticles enhanced the antibacterial activity of ceftazidime, being effective against E. coli and St. aureus.

Conclusion: Thus, the obtained drug delivery systems based on PHAs and chitosan in the form of microparticles can be promising means in treating infectious skin diseases for topical use.

Background and purpose: Disitamab vedotin is an antibody-drug conjugate (ADC) composed of a humanized IgG1 monoclonal antibody (mAb) targeting HER2 conjugated to monomethyl auristatin E(MMAE) via a cleavable dipeptide linker.

Experimental approach: The pharmacokinetics, distribution, catabolism/metabolism and elimination properties of disitamab vedotin and its payload MMAE were characterized in rats and tumour-bearing mice.

Key results: The configured mAb and total antibody showed linear dynamic characteristics. Moreover, the molecular structure of disitamab vedotin effectively reduces the exposure of MMAE, which has a fast clearance. Two radiolabeled probes were developed to track the fate of different components of the disitamab vedotin, including ¹²⁵I labelled antibody and ³H labelled MMAE payload of the ADC. Following a single intravenous administration of the radiolabeled probes to the tumour-bearing mice and rats, blood, various tissues, and excreta samples were collected and analyzed for radioactivity and to characterize the metabolites/catabolites. Disitamab vedotin and free MMAE (FM) were majorly distributed in tissues and organs with rich blood flow. Moreover, both disitamab vedotin and MMAE have higher and longer exposure in tumour tissue. Disitamab vedotin was mainly eliminated through renal excretion, while the FM was mainly eliminated through the biliary faecal route (>70 %) and a small fraction (<10 %) was eliminated through renal excretion in the form of catabolites/metabolites, among which, MMAE was identified as the major species, along with 10 other minor species.

Conclusion: These studies provided significant insight into disitamab vedotin pharmacokinetics, distribution, metabolism and elimination properties, which supports the clinical development of disitamab vedotin.

Background and purpose: Chemotherapy is the most effective and commonly utilized cancer treatment method. Therefore, studies on the sensitive determination of chemotherapy drugs used in cancer treatment can be very effective in improving treatment and reducing their side effects.

Experimental approach: The two-dimensional Co-based metal-organic framework nanosheets (2D Co-MOF NSs) were synthesized and then utilized to modify the screen-printed carbon electrode (2D Co-MOF NSs/SPCE). The 2D Co-MOF NSs/SPCE was successfully used for the determination of daunorubicin (DNR). Furthermore, we utilized differential pulse voltammetry, cyclic voltammetry, and chronoamperometry to evaluate the electrochemical properties of the created electrode.

Key results: The obtained results from CV studies demonstrate that this sensor exhibits outstanding electrocatalytic activity for the redox process of DNR. Under optimal experimental conditions, quantitative measurements resulted in a linear concentration range from 0.004 to 450.0 μM for DNR with a limit of detection (LOD) of 0.001 μM. Furthermore, the fabricated electrode was used for the simultaneous voltammetric detection of DNR and idarubicin (IDR). According to the results, the 2D Co-MOF NSs/SPCE sensor showed two well-defined peaks for the voltammetric oxidation of DNR and IDR. Eventually, the practical sample detection of DNR and IDR was successfully validated with acceptable results.

Conclusion: The developed sensing platform will be beneficial for enabling effective medical strategies to improve the clinical efficacy of chemotherapy drugs.

Background and purpose: The solubility of weakly-ionizable drugs in pure water, S_w, is commonly measured. The pH-dependent properties of the saturated solutions can be surprisingly complex in subtle ways. This commentary examines the characteristics of such measurements through case studies of 32 free acids, bases, and ampholytes (including crocetin, glibenclamide, mellitic acid, quercetin, bedaquiline, brigatinib, imatinib, celecoxib, and lysine), using published water solubility data.

Computational approach: Usually, in such saturated solutions, the ionic strength, I _w, is close to zero. When the pH is adjusted away from pH_w, the ionic strength increases, substantially in some cases (e.g. I _w > 10 M at pH 7.4 for mellitic acid and lysine). This change in ionic strength alters the activities of the species in solution. The corresponding equilibrium constants used to calculate the concentrations of these species must be adjusted accordingly. Here, the Stokes-Robinson hydration theory, slightly modified with Setschenow 'salting-out' constants to account for solvent interactions with unionized drugs, was used to estimate activity coefficients. The calculations were performed with the pDISOL-X program.

Key results: Given reliably-measured values of solubility in water (S _w) and ionization constant (pK _a) of the drugs and assuming that the Henderson-Hasselbalch equation is valid, a method is described for (i) adjusting the measured S _w values at ionic strength, I _w ~ 0 M, to values expected at reference ionic strength, I _ref = 0.15 M (or at any other reasonable reference value), (ii) determining the water pH_w in saturated solutions of added neutral-form drugs; (iii) determining the intrinsic solubility, S ₀, both at I _w and I _ref, and (iv) using analytic-continuation in the equilibrium mass action model to deduce the solubility values as a function of pH, harmonized to a selected I _ref. For highly soluble drugs, whose I _w exceeds 0.15 M, the intrinsic solubility values appear to depend on the amount of excess solid added.

Conclusion: This commentary re-emphasizes that measured S _w is not generally the same as S ₀. It is stressed that transforming measured drug solubility in pure water to an ionic strength level that is physiologically appropriate would better match the conditions found in biological media, potentially improving applications of solubility in pharmaceutical research and development.

Background and purpose: Sumatriptan is used to alleviate symptoms of migraine headaches, particularly during acute attacks. Naproxen is a medication that provides relief from pain, inflammation, and fever. Therefore, determination of them is important.

Experimental approach: In the present work, CoMoO₄ nanosheets were synthesized in a basic and easy way. A screen-printed graphite electrode's surface was altered using the as-prepared CoMoO₄ nanosheets' high electroactivity to create a CoMoO₄ nanosheets-modified screen-printed electrode (CoMoO₄ NSs-SPE), which was then employed for sumatriptan's electrochemical oxidation. Due to the superior electron transfer characteristics and catalytic activity of the produced CoMoO₄ nanosheets, the results demonstrated a notable improvement in sumatriptan's current responses. This study examined the electrochemical behavior of sumatriptan on the CoMoO₄ NSs-SPE utilizing a number of methods, including as chronoamperometry, cyclic voltammetry, and differential pulse voltammetry (DPV).

Key results: With a high sensitivity of 0.0718 μA/μM and a good correlation value of 0.9998, a linear calibration curve was obtained over a broad concentration range of 0.02-600.0 μM, suggesting a strong linear connection between the concentration and the response. Based on a signal-to-noise ratio of 3, the limit of detection for sumatriptan was determined to be 0.01 μM, suggesting a high degree of sensitivity for the detection technique. DPV results showed that the CoMoO₄ nanosheets-modified screen-printed electrode (CoMoO₄ NSs-SPE) could detect naproxen and sumatriptan at the same time.

Conclusion: The created sensor's usefulness and efficacy in real-world applications were demonstrated when it was successfully used to identify the target analytes in actual samples.

Background and purpose: This study aimed to explore the modification of screen-printed carbon electrode (SPCE) to produce an extensive conductive surface with gold nanoparticles (AuNPs) for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ribonucleic acid (RNA).

Experimental approach: The experiment was carried out using drop casting (DC) and spray coating (SC) methods. Au-S covalent interactions were formed between thiolated single-stranded DNA (ssDNA) and Au surface, which further hybridized with the target RNA to be detected using differential pulse voltammetry (DPV). Optimization of experimental conditions was performed using Box-Behnken design (BBD) on probe ssDNA concentration, probe ssDNA immobilization time, and target hybridization time. The morphology of the modified electrode was characterized using a scanning electron microscope, while the electrochemical behaviour was determined with DPV and electron impedance spectroscopy.

Key results: The results showed that SPCE modification with AuNPs by DC produced a higher peak current height of 12.267 μA with an R _ct value of 2.534 kΩ, while SC improved the distribution of AuNPs in the electrode surface. The optimum experimental conditions obtained using BBD were 0.5 μg mL^-1 ssDNA-probe concentration, an immobilization time of 22 minutes, and a hybridization time of 12 minutes. The limit of SARS-CoV-2 RNA detection at a concentration range of 0.5 to 10 μg mL^-1 was 0.1664 and 0.694 μg mL^-1 for DC and SC, respectively. The T-test results for both methods show that the current response of target RNA with SPCE/AuNP by DC does not show the same result, indicating a significant difference in the current response between those two methods.

Conclusion: SPCE/AuNP by DC is better than SPCE/AuNP by SC for immobilizing inosine-substituted ssDNA, which subsequently hybridizes with viral RNA, enabling label-free detection of guanine from SARS-CoV-2 RNA.

Background and purpose: Many new compounds are being prepared to overcome the problem of increasing microbial resistance and the increasing number of infections.

Experimental approach: This study includes a series of twenty-seven mono-, di- and trisubstituted 2-hydroxynaphthalene-1-carboxanilides designed as multitarget agents. The compounds are substituted with methoxy, methyl, and nitro groups, as well as additionally with chlorine, bromine, and trifluoromethyl at various positions. All the compounds were evaluated for antibacterial activities against Gram-positive and Gram-negative bacteria and mycobacteria. Cytotoxicity on human cells was also tested.

Key results: Three compounds showed activity comparable to clinically used drugs. N-(3,5-Dimethylphenyl)-2-hydroxynaphthalene-1-carboxamide (13) showed only antistaphylococcal activity (minimum inhibitory concentration (MIC) = 54.9 μM); 2-hydroxy-N-[2-methyl-5-(trifluoromethyl)phenyl]naphthalene-1-carboxamide (22) and 2-hydroxy-N-[4-nitro-3-(trifluoromethyl)phenyl]naphthalene-1-carboxamide (27) were active across the entire spectrum of tested bacteria/mycobacteria, both against the sensitive set and against resistant isolates (MICs range 0.3 to 92.6 μM). Compound 22 was even active against E. coli (MIC = 23.2 μM). The active agents showed no in vitro cytotoxicity up to a concentration of 30 μM.

Conclusion: Compounds with trifluoromethyl in the meta-anilide position, experimental lipophilicity expressed as log k (logarithm of the capacity factor) in the range of 0.31 to 0.34 and calculated electron σ parameter for the anilide substituent higher than 0.59 were effective. The investigated compounds meet the definition of Michael acceptors. Based on ADME screening, the investigated compounds 13, 22 and 27 should have suitable physicochemical parameters for good bioavailability in the organism. Therefore, these are promising agents for further study.

Background and purpose: Dopamine has an impact on the cardiovascular, endocrine, renal, and central neurological systems. Electrochemical techniques are becoming more and more popular among researchers as a way to assess dopamine and uric acid levels.

Experimental approach: Using electrochemical techniques, a new Universitet i Oslo MOF (UiO-66)-graphene oxide nanocomposite-modified carbon paste electrode was created to investigate the electrooxidation of uric acid and dopamine as well as their combinations. At the redesigned electrode, uric acid and dopamine were detected concurrently in a very sensitive way using differential pulse voltammetry (DPV).

Key results: Dopamine DPV peak currents increase in a linear fashion at doses between 0.05 and 600.0 μM.

Conclusion: Uric acid and dopamine levels in urine and dopamine injection samples may be determined with the help of the proposed sensor, which is reasonably priced and performs well.

Background and purpose: Cardiac mitochondria dysfunction plays a central pathophysiological role in the abnormal glucose metabolism in the heart during diabetic cardiomyopathy. The present study evaluated the effects of flavonoid glycoside naringin treatment on the interconnection between changes in cardiac mitochondria oxygen consumption, membrane potential and mitochondrial Ca²⁺ sensitivity during type 1 diabetes.

Experimental approach: Type 1 diabetes was induced by an intraperitoneal injection of streptozotocin (40 mg/kg) in rats and islet morphology, glucose and insulin levels, changes in heart mitochondria respiration, membrane potential, spontaneous and Ca²⁺ - induced mitochondrial permeability transition (MPT) pore opening were evaluated.

Key results: Diabetes resulted in typical signs of hyperglycaemia, which were accompanied by a rat cardiac mitochondria dysfunction, manifested by decreased V ₂ and V ₃ rates of oxygen consumption, while the initial membrane potential value remained unchanged. The rates of Ca²⁺-induced MPT pore opening and Ca²⁺-induced membrane potential dissipation in isolated mitochondria decreased under type 1 diabetes. The naringin treatment (40 mg/kg of the body weight, 4 weeks) partially recovered impaired cardiac mitochondria respiration, decreased spontaneous and increased Ca²⁺-induced MPT pore opening, improved pancreatic islets morphology and dystrophic changes, lowered glycated haemoglobin and blood plasma urea, and decreased the oxidative stress level with glucose or insulin concentrations remaining unchanged in diabetic animals.

Conclusions: Naringin administration demonstrated beneficial effects during type 1 diabetes and represents a promising therapeutic (or nutraceutical) approach for diabetes treatment.